Background: A substantial proportion of patients with AD show peripheral hyperinsulinemia and insulin resistance (reduced insulin efficiency) which down-regulates transport of insulin to the brain, and may increase neuropathological features of AD. AD is associated with reduced CSF insulin levels, and intravenous (IV) insulin administration (while maintaining euglycemia) improves memory, possibly by augmenting low brain levels or by overcoming insulin resistance. However, peripherally administered insulin is not a viable treatment due to risks associated with hypoglycemia. Following intranasal administration, insulin travels through extracellular pathways to the brain and largely bypasses the periphery, thereby circumventing the risk of hypoglycemia. Objective: We determined whether intranasal insulin administration produces a pattern of cognitive facilitation similar to that observed with acute intravenous insulin administration. Methods: On separate mornings, 26 memory-impaired subjects (13 with early AD and 13 with amnestic MCI) and 35 normal controls underwent 3 intranasal treatment conditions consisting of saline (placebo) or insulin (20 or 40 IU). Cognition was tested 15-minutes post-treatment, and blood was acquired at baseline and 45-minutes after treatment. Results: Percent change from saline was calculated for 20 and 40 IU doses. Insulin improved story recall for the MI/?4- group at both 20 and 40 IU doses (ps=.0006 and .001). The MI/?4- group also showed improved recall on the Buschke selective reminding test at the 40 IU dose (p=.03). Normal and MI/?4+ groups showed no improvement in story or list recall with insulin; in fact ?4+ patients showed reduced performance in the 40 IU condition (p<.05), which may indicate that we have exceeded the optimal dose for ?4+ subjects, who showed facilitation at very low insulin doses in previous work. Both AD and MCI patients responded similarly to insulin. Similarly, DRS scores were unrelated to change in story recall or list learning at either dose for the MI group, suggesting that benefits were independent of disease stage. No changes observed in plasma insulin or glucose levels. Conclusions: These findings suggest that intranasal insulin administration may have therapeutic benefit without the risk of peripheral hypoglycemia and provide further evidence for APOE related differences in insulin metabolism in AD.